TGF- β Promotes Metabolic Reprogramming in Lung Fibroblasts via mTORC1-dependent ATF4 Activation.

TGF-β Promotes Metabolic Reprogramming in Lung Fibroblasts via mTORC1-dependent ATF4 Activation.
Am J Respir Cell Mol Biol. 2020 Jul 15;:
Authors: O'Leary EM, Tian Y, Nigdelioglu R, Witt LJ, Cetin-Atalay R, Meliton AY, Woods PS, Kimmig LM, Sun KA, Gökalp GA, Mutlu GM, Hamanaka RB
Abstract
Idiopathic pulmonary fibrosis is a fatal disease characterized by the TGF-β-dependent differentiation of lung fibroblasts into myofibroblasts, leading to excessive deposition of collagen proteins and progressive scarring. We have previously shown that synthesis of collagen by myofibroblasts requires de novo synthesis of glycine, the most abundant amino acid found in collagen protein. TGF-β upregulates the expression of the enzymes of the de novo serine/glycine synthesis pathway in lung fibroblasts; however, the transcriptional and signaling regulators of this pathway remain incompletely understood. Here we demonstrate that TGF-β promotes accumulation of Activating Transcription Factor 4 (ATF4) which is required for increased expression of the serine/glycine synthesis pathway enzymes in response to TGF-β. We found that induction of the Integrated Stress Response (ISR) contributes to TGF-β-induced ATF4 activity; however, the primary driver of ATF4 downstream of TGF-β is activation of the Mechanistic Target of Rapamycin Complex 1 (mTORC1). TGF-β activates the PI3-kinase-Akt-mTOR pathway, and inhibition of PI3-kinase prevents activation of down...

Source: Am J Respir Cell Mol... - July 14, 2020 Category: Respiratory Medicine Authors: O'Leary EM, Tian Y, Nigdelioglu R, Witt LJ, Cetin-Atalay R, Meliton AY, Woods PS, Kimmig LM, Sun KA, Gökalp GA, Mutlu GM, Hamanaka RB Tags: Am J Respir Cell Mol Biol Source Type: research